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The objective of this study was to determine whether nelfinavir mesylate (<jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content>), a drug approved by the Food and Drug Administration (<jats:styled-content style=\"fixed-case\">FDA<\/jats:styled-content>) for treating <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content> infection, could be repurposed to treat pulmonary fibrosis in patients with systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Normal human lung, ventricular, and skin fibroblasts as well as lung fibroblasts from <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients were used to determine the effects of <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> on fibroblast\u2010to\u2010myofibroblast differentiation mediated by <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b21. The efficacy of <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> was also evaluated in an animal model of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c (bleomycin\u2010induced pulmonary fibrosis). In addition, in silico analysis was performed to determine novel off\u2010target effects of <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> inhibited <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b21\u2010mediated fibroblast\u2010to\u2010myofibroblast differentiation in lung fibroblasts through inhibition of the <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b21 canonical pathway. <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> also inhibited differentiation of skin and ventricular fibroblasts and adipocyte precursors into myofibroblasts. Activation of the <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b21\/mechanistic target of rapamycin pathway inhibited autophagy in lung fibroblasts, favoring collagen deposition, and <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> counteracted this effect in a dose\u2010dependent manner. Moreover, <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> significantly reduced lung injury and collagen deposition in an animal model of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c. In silico analysis of <jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> binding proteins revealed new putative beneficial mechanisms of action, consistent with known common pathways in fibrogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">NFV<\/jats:styled-content> abrogates <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b21\u2010mediated fibroblast\u2010to\u2010myofibroblast differentiation and pulmonary fibrosis through off\u2010target protein binding, a finding that supports consideration of this <jats:styled-content style=\"fixed-case\">FDA<\/jats:styled-content>\u2010approved medication as an antifibrotic agent.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40326","type":"journal-article","created":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T10:38:38Z","timestamp":1505990318000},"page":"115-126","source":"Crossref","is-referenced-by-count":16,"title":["The 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